ABCA7—A Member of the ABC Transporter Family in Healthy and Ailing Brain

Abstract

Identification of genetic markers of a human disease, which is generally sporadic, may become an essential tool for the investigation of its molecular mechanisms. The role of ABCA7 in Alzheimer’s disease (AD) was discovered less than ten years ago when meta-analyses provided evidence that rs3764650 is a new AD susceptibility locus. Recent research advances in this locus and new evidence regarding ABCA7 contribution to the AD pathogenesis brought a new understanding of the underlying mechanisms of this disorder. An interesting, up-to-date review article "ABCA7 and Pathogenic Pathways of Alzheimer’s Disease" by Aikawa et al. (2018), outlines the ABCA7 role in AD and summarizes new findings in this exciting area. ABC transporters or ATP-binding cassette transporters are a superfamily of proteins belonging to a cell transport system. Currently, members of the family are the focus of attention because of their central role in drug pharmacokinetics. Two recent findings are the reason why much attention is drawn to the ABCA7 family. First, is the biochemical data showing a role of ABCA7 in amyloid pathology. Second, genetic data identifying ABCA7 gene variants as loci responsible for the late-onset AD. These results point to the ABCA7 as a significant new contributor to the pathogenesis of AD.

Binding mode analysis of ABCA7 for the prediction of novel Alzheimer's disease therapeutics

“…It is large in size, consisting of 2,146 amino acids, comparable to the 2,261 and 2,273 amino acids of ABCA1 [96] and ABCA4 [97] , [98] , [99] , respectively. ABCA7 shares 52.8% and 48.2% sequence homology with ABCA1 and ABCA4, respectively, which is in agreement with the literature data (54% and 49%, respectively) [24] , [34] , [115] . Functionally, ABCA1 and ABCA7 are closely related, recognizing and translocating cholesterol and phospholipids [12] , [13] , [24] , [34] , while ABCA4 is mainly a retinoid transporter [12] .…”

“…ABCA7 shares 52.8% and 48.2% sequence homology with ABCA1 and ABCA4, respectively, which is in agreement with the literature data (54% and 49%, respectively) [24] , [34] , [115] . Functionally, ABCA1 and ABCA7 are closely related, recognizing and translocating cholesterol and phospholipids [12] , [13] , [24] , [34] , while ABCA4 is mainly a retinoid transporter [12] . Considering its greater similarity in terms of the amino acid sequence and its closer functional similarity, the generation of the ABCA7 homology model has been accomplished taking only the cryo-EM structure of ABCA1 into account [96] .…”

“…Most ABCA and ABCG transporters are cholesterol and/or phospholipid transporters that regulate cellular lipid homeostasis [11] , [12] , which is not only linked to membrane permeability and barrier function but also to human diseases, such as AD [6] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] . The lipid transporters ABCA1–2, ABCA5, ABCA7, ABCG1, and ABCG4 have particularly been associated with AD development [6] , [13] , [19] , [22] , [23] , [24] , [25] , [26] , [27] , [28] . Genetic variant association studies regarding ABCA1 have revealed controversial information related to certain single-nucleotide polymorphisms (SNPs) and AD [6] , [25] , [29] , [30] , [31] , [32] , [33] .…”

“…Genetic variant association studies regarding ABCA1 have revealed controversial information related to certain single-nucleotide polymorphisms (SNPs) and AD [6] , [25] , [29] , [30] , [31] , [32] , [33] . However, genome-wide association studies provided statistical proof that ABCA7 is strongly associated with AD development and/or progression [13] , [24] , [25] , [34] , [35] , [36] , [37] . Certain polymorphisms were associated with plaque formation in patients, which was correlated to an increased expression of ABCA7, supposedly as compensation for the increased Aβ load, suggesting an inhibition of Aβ deposition [22] .…”

“…Unfortunately, ABCA7 belongs to the so-called ‘under-studied’ ABC transporters that cannot be addressed by small-molecules [38] . Besides the substrates cholesterol and phospholipids [12] , [13] , [24] , [34] , the only small-molecules associated with ABCA7 are regulators of ABCA7 expression. These regulators include the inducers ponasterone A [39] , pravastatin [40] , [41] , and rosuvastatin [40] , as well as the downregulators digoxin [42] and 25-hydroxycholesterol [43] (all Fig.…”